The leading cause of death in cancer patients is intrinsic or acquired tumor resistance to chemotherapy. Tumors usually consist of mixed populations of malignant cells, some of which are drug sensitive while others are drug resistant. Chemotherapy that effectively kills drug sensitive cells or sensitizes tumor cells for radiotherapy has little effect on cells that have acquired drug resistance.
Lung carcinomas are the leading cause of cancer deaths in the United States and worldwide in both men and women. Chemotherapy for non-small-cell lung carcinoma (NSCLC), which accounts for approximately 85% of lung cancer cases, remains marginally effective. The major contributing factor to the failure of chemotherapy in lung cancer is the development of drug resistance.
Cancer cells have higher expression of Phase II enzymes and Phase III drug efflux proteins, both of which detoxify drugs. Phase II enzymes include the family of glutathione S-transferase enzymes, glutathione biosynthetic genes, UDP-glucoronosyltransferases (UGT), members of the aldo keto reductase superfamily, and several antioxidants that are involved in the detoxification of a broad spectrum of anti-cancer drugs. The multidrug resistance (MDR) proteins are ATP binding cassette transporters, and belong to the Phase III drug efflux class of proteins. The MDR proteins act as molecular pumps in the tumor cell membrane, actively expelling chemotherapy drugs from the interior of the cell, and allowing the tumor cell to subvert the chemotherapeutic effects of the administered compounds. Several studies have shown that the expression of Phase II genes [glutathione-S-transferases (GSTs)], antioxidants [glutathione (GSH)], and drug efflux proteins [multidrug resistance protein (MRP) family] are increased in NSCLC. Phase II detoxification enzymes in conjunction with Phase III drug efflux proteins act to detoxify cancer drugs, whereas antioxidants confer cytoprotection by attenuating drug-induced oxidative stress and apoptosis.
Presently, chemoresistance presents an obstacle to the treatment of cancer, and treatment options for subjects with multi drug resistant tumors are limited. Thus, there is an urgent need for methods of identifying and treating chemoresistant tumors.